Abundant Fas expression by gastrointestinal stromal tumours may serve as a therapeutic target for MegaFasL.
Although the tyrosine kinase inhibitor imatinib has been shown to be an active agent in patients with gastrointestinal stromal tumours (GIST), complete remissions are almost never seen and most patients finally experience disease progression during their course of treatment. An alternative therapeutic option is to target death receptors such as Fas. We showed that a panel of imatinib-sensitive (GIST882) and imatinib-resistant (GIST48, GIST430 and GIST430K-) cell lines expressed Fas. MegaFasL, a recently developed hexameric form of soluble Fas ligand (FasL), appeared to be an active apoptosis-inducing agent in these cell lines. Moreover, MegaFasL potentiated the apoptotic effects of imatinib. Immunohistochemical evaluations, in 45 primary GISTs, underscored the relevance of the Fas pathway: Fas was expressed in all GISTs and was expressed strongly in 93%, whereas FasL was expressed at moderate and strong levels in 35 and 53% of GISTs, respectively. Fas and FasL expression were positively correlated in these primary GISTs, but there was no association between Fas or FasL expression and primary site, histological subtype, tumour size, mitotic index, risk classification, and KIT mutation status. The abundant immunohistochemical Fas and FasL expression were corroborated by western blot analysis. In conclusion, our data implicate Fas as a potential therapeutic target in GIST.
Rikhof
B
B
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
van der Graaf
W T A
WT
Meijer
C
C
Le
P T K
PT
Meersma
G J
GJ
de Jong
S
S
Fletcher
J A
JA
Suurmeijer
A J H
AJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000627:therapeutic use*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D019014:fas Receptor / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D001549:Benzamides; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D010879:Piperazines; D011743:Pyrimidines; D019014:fas Receptor; D000068877:Imatinib Mesylate